Intercellular cell-adhesion molecule-1 (ICAM-1) is up-regulated on the vascular endothelium in response to pro-inflammatory cytokines produced in the synovial cavity of patients with Rheumatoid Arthritis. Nanoparticles that interact specifically with ICAM-1 may preferentially pool to sites of inflammation potentially interrupting this signal and/or facilitating the delivery of therapeutics such as methotrexate. The objective of this application is to identify the performance of methotrexate loaded nanoparticles targeted to ICAM-1 for rescuing rodents with collagen-induced arthritis (CIA). Our central hypothesis is that nanoparticles loaded with 10% methotrexate will significantly reduce arthritis scores in the CIA rodent model compared to an equivalent intravenous dose of methotrexate or nanoparticles alone. We propose two Specific Aims: Specific Aim #1: Identify nanoparticle formulations that specifically target ICAM-1 on HUVECs. Our working hypothesis, based upon strong preliminary data, is that nanoparticles displaying the cLABL peptide will preferentially bind HUVECs overexpressing ICAM-1. Specific Aim #2: Identify cLABL-nanoparticle disease mitigation in the CIA rodent model. Our working hypothesis, also based upon strong preliminary data, is that cLABL-nanoparticles targeted to ICAM-1 and delivering methotrexate will significantly disrupt the progression of CIA compared to methotrexate or cLABL-nanoparticles alone. The FDA has approved combination therapy using mAbs against TNF-a (infliximab) with methotrexate and results have been encouraging. Here, we propose a potentially more selective approach for treating RA by attempting to localize drugs to molecular markers of inflammation (ICAM-1) as an alternative to systemic immunosuppression.